The general aim of my research is to develop the capacity to regulate or manipulate the cytolytic T lymphocyte (CTL) response; especially, the CTL response to viral infections and malignancies. In order to accomplish this more general goal I feel that it will be necessary to define on a molecular level the antigenic requirements for triggering CTLs and the cellular interactions that lead to CTL induction. The CTLs generated (the products of antigen triggering) must be better defined in terms of the antigens their receptors recognize and eventually the receptors from these CTLs must be isolated and characterized biochemically. The specific aims of this proposal, therefore, are as follows: (1) to identify, isolate and purify the viral and major histocompatibility complex (MHC) antigens involved in CTL triggering; (2) to define the site(s) on these viral and MHC molecules that is recognized by the CTL; (3) to define the relationship of the viral antigens and MHC antigens to each other; (4) to define some of the cellular requirements for CTL triggering; (5) to define the specificity of the CTLs that result from the antigen triggering event; and (6) to isolate and characterize the T cell receptors from these CTLs. In order to investigate the CTL response on a molecular level, better defined and more specific probes are required. Recent methodological developments make it possible: (1) to construct better defined antigens to investigate CTL triggering. MHC antigens that retain CTL stimulating activity can be isolated and purified. When inserted into artificial membranes or liposomes, one can investigate the CTL response to these defined antigens rather than to the whole cell. (2) The ability to produce monoclonal CTL lines now seems feasible and these monoclonal lines may prove to be a powerful probe for studying the specificity of the CTL response. In this proposal I will utilize these methods to investigate the specific aims outlines.